Herp regulates intracellular survival of Mycobacterium tuberculosis H37Ra in macrophages by regulating reactive oxygen species-mediated autophagy

Abstract

ABSTRACT Novel treatment strategies for tuberculosis (TB), such as host-directed therapeutics, may offer therapeutic options for patients with drug-resistant TB. Endoplasmic reticulum (ER) stress-mediated apoptosis is one of the host defense mechanisms used to remove mycobacteria. It is reported that homocysteine-inducible ER protein with ubiquitin-like domain 1 (Herp) inhibits apoptosis by preventing the loss of ER Ca2+ and mitochondrial potential during ER stress. However, the roles of Herp in ER stress and apoptosis during H37Ra infection are largely unknown. Here, we show that Herp is induced in H37Ra-infected macrophages through an activating transcription factor 6 (ATF6)-dependent ER stress response. Suppressing Herp by genetic approaches decreased production of HRD1, conserved branch of mammalian ER-associated degradation (ERAD) machinery, and increased the production levels of ER stress-associated molecules such as p-IRE1ɑ and BiP after H37Ra infection. Suppressing Herp also increased both the NADPH oxidase 2 and inositol triphosphate receptor, which sequentially led to increased reactive oxygen species (ROS) production during H37Ra infection. Interestingly, the Herp depletion-mediated ROS increment led to autophagy induction, which led to decreased intracellular survival of mycobacteria in H37Ra-infected macrophages. The role of Herp was further confirmed by the fact that blocking this molecule in vitro and in vivo significantly reduced mycobacterial survival. These findings indicate that Herp mediates crosstalk between ER stress and ROS-mediated autophagy during H37Ra infection, suggesting the potential of Herp manipulation as a therapeutic strategy for Mycobacterium tuberculosis (Mtb) infection. IMPORTANCE Several studies have suggested that endoplasmic reticulum (ER) stress is important in the pathogenesis of infectious diseases; however, the precise function of ER stress regulation and the role of Herp as a regulator in Mtb H37Ra-induced ER stress remain elusive. Therefore, our study investigated ER stress and autophagy associated with Herp expression in Mycobacterium tuberculosis-infected macrophages to determine the role of Herp in the pathogenesis of tuberculosis.

Keywords

• ER stress
• Mycobacterium tuberculosis
• homocysteine-inducible ER protein with ubiquitin-like domain 1
• reactive oxygen species
• ER-associated degradation
• autophagy